Patent GB-831345-A (GB)
Title: Substituted piperidines
Inventor: YOUNG EDWIN HARRY PATERSON
Filed: 1957-02-13
Abstract: The invention comprises compounds of the general formula <FORM:0831345/IV (b)/1> and their pharmaceutically acceptable acid addition and quaternary salts, wherein R stands for a hydrogen atom, or for a lower alkyl or alkenyl radical (up to 6 carbon atoms) optionally substituted by a hydroxy group or a halogen atom, R1 and R2 stand for methyl groups, and R3 stands for a lower alkyl group (1-6 carbon atoms), and wherein R, R1, R2 and R3 together contain at least 4 carbon atoms, and the preparation thereof by (1) reducing compounds of the general formula <FORM:0831345/IV (b)/2> preferably by heating with amalgamated zinc and hydrochloric acid or by heating the corresponding hydrazone with sodium or potassium ethoxide or with sodium or potassium hydroxide in the presence of an inert diluent such as di- or triethylene glycol; (2) (when R is other than hydrogen) alkylation or alkenylation of a compound of the general formula <FORM:0831345/IV (b)/3> either with an alkyl or alkenyl halide or an alkyl sulphonate in the presence of an acid-binding agent or, when the alkylation is methylation, with formaldehyde and formic acid, or, when the process is b -hydroxyethylation, with epichlorhydrin; (3) (when R is alkyl) reduction of compounds of the general formula <FORM:0831345/IV (b)/4> wherein R4 stands for an acyl or an alkenyl group, preferably by means of lithium aluminium hydride or hydrogen in the presence of Adam's platinum catalyst; (4) (wherein R is an alkyl radical containing a terminal chlorine substituent) chlorinating the corresponding compounds wherein R stands for an alkyl group containing a terminal hydroxy group, preferably with thionyl chloride, in the presence of an inert solvent such as benzene; and (5) quaternisation of the corresponding tertiary bases preferably by an alkyl halide such as methyl iodide in the presence of an inert solvent such as ether.  Examples describe the p preparation of 2:2 - dimethyl - 6 - ethyl -, - 6 - n - propyl - and - 6 - isopropylpiperidines and their hydrochlorides by process (1), 1 : 2 : 2 : 6-tetramethylpiperidine, 6 - ethyl -, and 6 - isopropyl - 1 : 2 : 2 - trimethylpiperidines, 1-allyl -, and 1 - ethyl - 2 : 2 : 6 - trimethyl piperidines and their hydrochlorides and 1-b -hydroxyethyl - 2 : 2 : 6 - trimethylpiperidine by process (2), 1 - propyl -, and 1 - ethyl - 2 : 2 : 6-trimethylpiperidine and their hydrochlorides by process (3), 1 - b  - chloroethyl - 2 : 2 : 6 - trimethylpiperidine hydrochloride by process (4), and 1 : 1 : 2 : 2 : 6 - pentamethylpiperidinium iodide by process (5).  The Provisional Specification further discloses that the groups R and R3 may additionally be substituted, that the groups R1 and R2 may be hydrocarbon radicals, which additionally may be substituted, for example by an hydroxy radical, and the piperidine ring may contain in addition to the substituents already present, halogen atoms or amino, acylamino, alkoxy, or hydrocarbon radicals, which may themselves be substituted by hydroxy or alkoxy radicals or halogen atoms, and that the compounds of the invention may be produced by reduction of the corresponding 4-halogenopiperidines, for example with a zinc-copper couple, or by reduction of the corresponding 1 : 2 : 5 : 6-tetra hydropyridine.  1 - Acetyl - 2 : 2 : 6 - trimethyl pyridine is prepared from acetic anhydride and 2 : 2 : 6-trimethyl pyridine, and tetrahydro pyridines are prepared by treating 4-piperidones with a Grignard reagent or an acetylenic compound to give the 4-piperidol which is dehydrated.